Projects / Programmes
Heterologous polyketide production system based on super-producing industrial streptomycete strains
| Code |
Science |
Field |
Subfield |
| 4.06.00 |
Biotechnical sciences |
Biotechnology |
|
| Code |
Science |
Field |
| T490 |
Technological sciences |
Biotechnology |
Streptomycetes, heterologous polyketide antibiotics, expression system, recombinant DNA technology, industrial super-producing strains
Researchers (1)
| no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
| 1. |
21392 |
PhD Štefan Fujs |
Biotechnology |
Head |
2008 - 2010 |
87 |
Organisations (1)
Abstract
Current estimated market for natural product derived pharmaceuticals is in excess of $40 billion, with polyketides and its semi-synthetic derived compounds accounting for over $17 billion annually. Polyketides are secondary metabolites of diverse chemical structures and a broad range of biological activities, such as antibacterial erythromycin, antifungal nystatin, immunosuppressive FK506, anticancer doxorubicin, cholesterol-lowering agent lovastatin, and other pharmacological activities, of medical and industrial importance, produced by microorganisms, particularly by actinomycete soil bacteria. Despite their wide medical and commercial importance, polyketide drugs are still primarily produced with expensive and laborious synthetic processes, or biosynthetically in their native bacterial hosts, which are often constrained by low yields, slow growth characteristics and poor susceptibility to genetic manipulation. A number of novel microorganisms producing natural products with very promising biological activities have been identified of which many are very difficult or impossible to cultivate. Almost entirely unexploited novel approach of “metagenomics”, targeting predominantly unculturable microorganisms has been developed during the last decade. The “metagenomic” approach has been recently significantly reinforced by the effective genome mining of available genomic information greatly improved by the economically amenable and rapid DNA sequencing which has revealed huge number and diversity of unknown genes or gene clusters with exceptional medical and commercial potential. The expanding knowledge of Streptomyces genetics has also led us to the development of powerful new technologies of combinatorial and biosynthetic engineering which are generating a numerous novel »unnatural« natual analogues, unfortunatelly, often hindered with low productivity of recombinant enzymes. All these facts clearly present that there is a strong requirement for a reliable and robust system for high-level expression of existing or novel secondary metabolites (polyketides) and often unknown biosynthetic clusters in heterologous hosts. The production of polyketides using a Streptomyces-based expression system for heterologous production of PKS or NRPS based on high-producing industrial Streptomyces strains and processes, which have been carefully developed over the years, may offer many advantages over natural producers. Therefore, the aim of this proposed project is to construct a robust platform for heterologous polyketide expression based on industrial Streptomyces »super-producing« strains, which will represent potentially very powerful and commercially valuable technology, and will be essential for the future production of novel polyketide natural products of medical importance.
Significance for science
The objective of this research project was to construct a heterologous expression system for medicinally important polyketide metabolites using known industrial high-producing Streptomyces strains and processes. Polyketides and their semi-synthetically modified natural products represent a large group of biologically active compounds with high clinical and commercial significance. . Polyketides, despite their wide medical and commercial importance, are still primarily produced using classical biosynthetic processes and/or classical semi-synthetic chemistry approaches with high costs and environmental burden. Industrial microbial strains are constrained by low yields and complex bioprocesses. Furthermore, efforts of researchers in pharmaceutical industry are often hampered by poor susceptibility of these strains to genetic manipulation. Novel approaches such as combinatorial and biosynthetic engineering as well as novel metagenomics approaches, coupled with the effective genome mining of available genomic information, constantly bring exciting new biologically active and medicinally important compounds and drug candidates. A number of novel microorganisms producing natural products with very promising biological activities have been identified of which many are very difficult or impossible to cultivate in industrial scale (“the unculturables”). All this clearly demonstrates that there is a strong requirement for a reliable and robust system for high-level expression of existing or novel currently unknown biosynthetic clusters in heterologous hosts. Therefore, necessary genetic tools were successfully developed and methods adapted to high-yield industrial host strains. This platform based on industrial polyketide super-producing Streptomyces hosts, reinforced with novel tools and methods applicable for heterologous expression of PKS systems and represents a potentially very powerful and industrially applicable technology for production of novel polyketide natural products of medical importance.
Significance for the country
The development of robust and reliable platform for heterologous production of existing or novel medically important polyketides brings important technological progress for the biotech company Acies Bio, providing additional competitive advantage in the field of pharmaceutical biotechnology. In addition, the development of this platform will benefit Slovenian pharmaceutical industry in general, as the platform is intended specifically towards improved heterologous production of generic pharmaceutical products, which account for an important part of activities of Slovenian pharmaceutical companies. The project “Heterologous polyketide production system based on super-producing industrial streptomycete strains” was carried out in collaboration with the Biotechnical faculty of the University of Ljubljana. In the scope of this project, undergraduate and graduate students of the University of Ljubljana were actively involved, which directly stimulated research and teaching activities in the field of industrial microbiology and microbial biotechnology as well as allowed for knowledge transfer between academia and industry.
Most important scientific results
Annual report
2008,
final report,
complete report on dLib.si
Most important socioeconomically and culturally relevant results
Annual report
2008,
final report,
complete report on dLib.si
